lecture 28 marijuana & nero transmitters

8/8/2019 LECTURE 28 Marijuana & Nero Transmitters

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68 SCIENTIFIC AMERICAN DECEMBER 2004COPYRIGHT 2004 SCIENTIFIC AMERICAN, INC.


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marijuana

the

brainsownResearch into natural chemicals that

mimic marijuanas effects in the brain

could help to explainand suggesttreatments forpain, anxiety, eating

disorders, phobias and other conditions

By Roger A. Nicoll

and Bradley E. Alger

COPYRIGHT 2004 SCIENTIFIC AMERICAN, INC.


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Marijuana is a drug with a mixed history. Men-

tion it to one person, and it will conjure images of

potheads lost in a spaced-out stupor. To another,

it may represent relaxation, a slowing down of

modern madness. To yet another, marijuana means hope for

cancer patients suffering from the debilitating nausea of che-

motherapy, or it is the promise of relief from chronic pain. Thedrug is all these things and more, for its history is a long one,

spanning millennia and continents. It is also something every-

one is familiar with, whether they know it or not. Everyone

grows a form of the drug, regardless of their political leanings

or recreational proclivities. That is because the brain makes its

own marijuana, natural compounds called endocannabinoids

(after the plants formal name, Cannabis sativa).

The study of endocannabinoids in recent years has led to

exciting discoveries. By examining these substances, research-

ers have exposed an entirely new signaling system in the brain:

a way that nerve cells communicate that no one anticipated

even 15 years ago. Fully understanding this signaling systemcould have far-reaching implications. The details appear to hold

a key to devising treatments for anxiety, pain, nausea, obesity,

brain injury and many other medical problems. Ultimately such

treatments could be tailored precisely so that they would not ini-

tiate the unwanted side effects produced by marijuana itself.

A Checkered Pastmarijuana and its various alter egos, such as bhang

and hashish, are among the most widely used psychoactive

drugs in the world. How the plant has been used varies by cul-

ture. The ancient Chinese knew of marijuanas pain-relieving

and mind-altering effects, yet it was not widely employed for

its psychoactive properties; instead it was cultivated as hemp

for the manufacture of rope and fabric. Likewise, the ancient

Greeks and Romans used hemp to make rope and sails. In

some other places, however, marijuanas intoxicating proper-

ties became important. In India, for example, the plant was

incorporated into religious rituals. During the Middle Ages,

its use was common in Arab lands; in 15th-century Iraq it was

used to treat epilepsy; in Egypt it was primarily consumed as

an inebriant. After Napoleons occupation of Egypt, Europe-

ans began using the drug as an intoxicant. During the slave

trade, it was transported from Africa to Mexico, the Carib-

bean and South America.

Marijuana gained a following in the U.S. only relatively

recently. During the second half of the 19th century and the

beginning of the 20th, cannabis was freely available without a

prescription for a wide range of ailments, including migraine

and ulcers. Immigrants from Mexico introduced it as a rec-

reational drug to New Orleans and other large cities, where

it became popular among jazz musicians. By the 1930s it had

fallen into disrepute, and an intense lobbying campaign de-

monized reefer madness. In 1937 the U.S. Congress, against

the advice of the American Medical Association, passed the

Marijuana Tax Act, effectively banning use of the drug by

making it expensive and difficult to obtain. Ever since, mari-

juana has remained one of the most controversial drugs inAmerican society. Despite efforts to change its status, it re-

mains federally classified as a Schedule 1 drug, along with

heroin and LSD, considered dangerous and without util ity.

Millions of people smoke or ingest marijuana for its in-

toxicating effects, which are subjective and often described

as resembling an alcoholic high. It is estimated that ap-

proximately 30 percent of the U.S. population older than 12

have tried marijuana, but only about 5 percent are current us-

ers. Large doses cause hallucinations in some individuals but

simply trigger sleep in others. The weed impairs short-term

memory and cognition and adversely affects motor coordina-

70 SCIENTIFIC AMERICAN DECEMBER 2004

C

O

O

OH

OH

C

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CH3

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H3C

H3C

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Marijuana and related drugs affect behavior by actingon receptors for compounds called endocannabinoidsthat are produced by the brain.

These endocannabinoids participate in regulating pain,anxiety, hunger and vomiting, among other processes.This wide range of effec ts explains why the use ofmarijuana seems to elicit so many different responses.

By developing drugs that can mimic specific beneficialactions of endocannabinoidswithout triggering someof the adverse effects of marijuanaresearchers hopeto find new treatments for diverse problems.

Overview/Brains Marijuana

DESPITE DIFFERENCES in their structures, THC, produced by themarijuana plant, and the brain chemicals ananda mide and 2-AG canall activate the same r eceptor (CB1) in the brain.

Delta-9-Tetrahydrocannabinol (THC)

Anandamide

2-Arachidonoyl glycerol (2-AG)



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tion, although these setbacks seem to be reversible once the

drug has been purged from the body. Smoking marijuana also

poses health risks that resemble those of smoking tobacco.

On the other hand, the drug has clear medicinal bene-

fits. Marijuana alleviates pain and anxiety. It can prevent

the death of injured neurons. It suppresses vomiting and en-

hances appetiteuseful features for patients suffering the

severe weight loss that can result from chemotherapy.

Finding the Responsible Agentfiguring out how the drug exerts these myriad effects

has taken a long time. In 1964, after nearly a century of work

by many individuals, Raphael Mechoulam of the Hebrew Uni-

versity in Jerusalem identified delta-9-tetrahydrocannabinol(THC) as the compound that accounts for virtually all the

pharmacological activity of marijuana. The next step was to

identify the receptor or receptors to which THC was binding.

Receptors are small proteins embedded in the membranes

of all cells, including neurons, and when specific molecules bind

to themfitting like one puzzle piece into anotherchanges in

the cell occur. Some receptors have water-filled pores or chan-

nels that permit chemical ions to pass into or out of the cell.

These kinds of receptors work by changing the relative voltage

inside and outside the cell. Other receptors are not channels but

are coupled to specialized proteins called G-proteins. These

G-protein-coupled receptors represent a large family that set

in motion a variety of biochemical signaling cascades within

cells, often resulting in changes in ion channels.

In 1988 Allyn C. Howlett and her colleagues at St. Louis

University attached a radioactive tag to a chemical deriva-

tive of THC and watched where the compound went in rats

brains. They discovered that it attached itself to what came

to be called the cannabinoid receptor, also known as CB1.

Based on this finding and on work by Miles Herkenham of

the National Institutes of Health, Lisa Matsuda, also at the

NIH, cloned the CB1 receptor. The importance of CB1 in the

action of THC was proved when two researchers working

independentlyCatherine Ledent of the Free University of

Brussels and Andreas Zimmer of the Laboratory of Molecu-lar Neurobiology at the University of Bonnbred mice that

lacked this receptor. Both investigators found that THC had

virtually no effect when administered to such a mouse: the

compound had nowhere to bind and hence could not trigger

any activity. (Another cannabinoid receptor, CB2, was later

discovered; it operates only outside the brain and spinal cord

and is involved with the immune system.)

As researchers continued to study CB1, they learned that

it was one of the most abundant G-protein coupled receptors

in the brain. It has its highest densities in the cerebral cortex,

hippocampus, hypothalamus, cerebellum, basal ganglia, brain

www.sciam.com SCIENTIFIC AMERICAN 71

CEREBELLUMCenter for motor controland coordination

HYPOTHALAMUSControls appetite,hormonal levels andsexual behavior

AMYGDALAResponsible foranxiety, emotionand fear

HIPPOCAMPUSImportant for memoryand the learning offacts, sequences andplaces

BRAIN STEM AND SPINAL CORDImportant in the vomiting reflexand the sensation of pain

NEOCORTEXResponsible for highercognitive functions andthe integration ofsensory information

BASAL GANGLIAInvolved in motorcontrol andplanning, as well asthe initiation andtermination of action

WHERE MARIJUANA ACTSThe drug Cannabis sativa binds to the brains own cannabinoidreceptors in many different areas, including those highlightedbelow. This widespread influence accounts for the diverse eff ects

the drugand its relatives made by the braincan have andoffers exciting opportunities for devising medications that canspecifically target certain sites to control, say, appetite or pain.



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stem, spinal cord and amygdala. This distribution explains

marijuanas diverse effects. Its psychoactive power comes from

its action in the cerebral cortex. Memory impairment is rooted

in the hippocampus, a structure essential for memory forma-

tion. The drug causes motor dysfunction by acting on move-

ment control centers of the brain. In the brain stem and spinal

cord, it brings about the reduction of pain; the brain stem also

controls the vomiting reflex. The hypothalamus is involved

in appetite, the amygdala in emotional responses. Marijuana

clearly does so much because it acts everywhere.

Over time, details about CB1s neuronal location emerged

as well. Elegant studies by Tams F. Freund of the Institute

of Experimental Medicine at the Hungarian Academy of Sci-

ences in Budapest and Kenneth P. Mackie of the University of

Washington revealed that the cannabinoid receptor occurred

only on certain neurons and in very specific positions on those

72 SCIENTIFIC AMERICAN DECEMBER 2004

RETROGRADE SIGNALINGResearchers have found that endogenous cannabinoids (endo-cannabinoids) participate in retrograde signaling, a previouslyunknown form of communication in the brain. Rather thanflowing forward in the usual way from a presynaptic (neuro-transmitter-emitting) neuron to a postsynaptic (recipient)

one, endocannabinoids work backward, traveling from thepostsynaptic cell to the presynaptic one. The endocannabinoid2-AG released from a postsynaptic cell can, for example, causea presynaptic cell to decrease its secretion of the inhibitoryneurotransmitter GABA onto the postsynaptic cell (diagrams).

CB1 receptor

Signal

Presynaptic neurons

Signal

Synapse

GABA

Glutamate

Glutamatereceptor

Excitatorysignal Postsynaptic neuron

Closedcalcium

channelGABAreceptor

Inhibitory signalNeuron doesnot fire

Presynaptic neurons

CB1 receptor

Signal

Signal

Glutamate

Glutamatereceptor

GABAreceptor

Excitatorysignal Postsynaptic neuron

Opencalciumchannel

If GABA from a presynaptic neuron hits a postsynaptic cell at thesame time as excitatory signals (such as those carried by theneurotransmitter glutamate) reach the same cell ( above), the GABAcan block the postsynaptic cell from firing. If, however, changes incalcium levels in the postsynaptic neuron trigger the production of

2-AG (below), this endocannabinoid will travel back to its receptor(CB1) on the GABA-producing neuron. In a process known asdepolarized-induced suppression of inhibition (DSI), it will thenprevent the release of GABA and thus allow the excitatory signals toactivate the pos tsynaptic cell.

Neuron fires

Inhibitorysignal

2-AG



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neurons. It was densely packed on neurons that released GABA(gamma-aminobutyric acid), which is the brains main inhibi-

tory neurotransmitter (it tells recipient neurons to stop firing).

CB1 also sat near the synapse, the contact point between two

neurons. This placement suggested that the cannabinoid re-

ceptor was somehow involved with signal transmission across

GABA-using synapses. But why would the brains signaling

system include a receptor for something produced by a plant?

The Lesson of Opiumthe same question had arisen in the 1970s about mor-

phine, a compound isolated from the poppy and found to bind

to so-called opiate receptors in the brain. Scientists finally dis-covered that people make their own opioidsthe enkephalins

and endorphins. Morphine simply hijacks the receptors for the

brains opioids.

It seemed likely that something similar was happening

with THC and the cannabinoid receptor. In 1992, 28 years

after he identified THC, Mechoulam discovered a small fatty

acid produced in the brain that binds to CB1 and that mimics

all the activities of marijuana. He named it anandamide, af-

ter the Sanskrit word ananda, bliss. Subsequently, Daniele

Piomelli and Nephi Stella of the University of California at

Irvine discovered that another lipid, 2-arachidonoyl glycerol

(2-AG), is even more abundant in certain brain regions than

anandamide is. Together the two compounds are considered

the major endogenous cannabinoids, or endocannabinoids.

(Recently investigators have identified what look like other

endogenous cannabinoids, but their roles are uncertain.) The

two cannabinoid receptors clearly evolved along with endo-

cannabinoids as part of natural cellular communication sys-

tems. Marijuana happens to resemble the endocannabinoids

enough to activate cannabinoid receptors.

Conventional neurotransmitters are water-soluble and are

stored in high concentrations in little packets, or vesicles, as

they wait to be released by a neuron. When a neuron fires,

sending an electrical signal down its axon to its tips (pre-

synaptic terminals), neurotransmitters released from vesiclescross a tiny intercellular space (the synaptic cleft) to recep-

tors on the surface of a recipient, or postsynaptic, neuron. In

contrast, endocannabinoids are fats and are not stored but

rather are rapidly synthesized from components of the cell

membrane. They are then released from places all over the

cells when levels of calcium rise inside the neuron or when

certain G-protein-coupled receptors are activated.

As unconventional neurotransmitters, cannabinoids pre-

sented a mystery, and for several years no one could figure

out what role they played in the brain. Then, in the early

1990s, the answer emerged in a somewhat roundabout fash-

ion. Scientists (including one of us, Alger, and his colleagueat the University of Maryland School of Medicine, Thomas

A. Pitler) found something unusual when studying pyrami-

dal neurons, the principal cells of the hippocampus. After

calcium concentrations inside the cells rose for a short time,

incoming inhibitory signals in the form of GABA arriving

from other neurons declined.

At the same time, Alain Marty, now at the Laboratory of

Brain Physiology at the Ren Descartes University in Paris,

and his colleagues saw the same action in nerve cells from

the cerebellum. These were unexpected observations, because

they suggested that receiving cells were somehow affecting

transmitting cells and, as far as anyone knew, signals in ma-ture brains flowed across synapses in one way only: from the

presynaptic cell to the postsynaptic one.

A New Signaling Systemit seemed possible that a new kind of neuronal commu-

nication had been discovered, and so researchers set out to un-

derstand this phenomenon. They dubbed the new activity DSI,

for depolarization-induced suppression of inhibition. For DSI

to have occurred, some unknown messenger must have traveled

from the postsynaptic cell to the presynaptic GABA-releasing

one and somehow shut off the neurotransmitters release.

Such backward, or retrograde, signaling was known to

occur only during the development of the nervous system. If it

were also involved in interactions among adult neurons, that

would be an intriguing findinga sign that perhaps other pro-

cesses in the brain involved retrograde transmission as well.

Retrograde signaling might facilitate types of neuronal infor-

mation processing that were difficult or impossible to accom-

plish with conventional synaptic transmission. Therefore, it

was important to learn the properties of the retrograde signal.

Yet its identity remained elusive. Over the years, countless mol-

ecules were proposed. None of them worked as predicted.

Then, in 2001, one of us (Nicoll) and his colleague at

the University of California at San Francisco, Rachel I. Wil-

sonand at the same time, but independently, a group led byMasanobu Kano of Kanazawa University in Japanreported


As unconventional neurotransmitters, CANNABINOIDSpresented a mystery, and for several years no onecould figure out WHAT ROLE THEY PL AYED in the brain.

ROGER A. NICOLL and BRADLEY E. ALGER first worked together

in the late 1970s, when they both were forming what has be-

come an enduring interest in synaptic transmission. At that

time, Nicoll had just moved to the University of California, San

Francisco, where he is now pro fessor of pharmacology; Alger,

currently pro fessor of physiology and psychiatry at the Univer-

sity of Maryland School of Medicine, was his first postdoctoral

fellow. Nicoll is a member of the National Academy of Sciences

and recent winner of the Heinrich Wieland Award.

THEA

UTHORS



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minders of past experiences. The discoveries raise the possi-

bility that abnormally low numbers of cannabinoid receptors

or the faulty release of endogenous cannabinoids are involved

in post-traumatic stress syndrome, phobias and certain forms

of chronic pain. This suggestion fits with the fact that some

people smoke marijuana to decrease their anxiety. It is also

conceivable, though far from proved, that chemical mimics ofthese natural substances could allow us to put the past behind

us when signals that we have learned to associate with certain

dangers no longer have meaning in the real world.

Devising New Therapiesthe repertoire of the brains own marijuana has not

been fully revealed, but the insights about endocannabinoids

have begun helping researchers design therapies to harness

the medicinal properties of the plant. Several synthetic THC

analogues are already commercially available, such as nabi-

lone and dronabinol. They combat the nausea brought on by

chemotherapy; dronabinol also stimulates appetite in AIDSpatients. Other cannabinoids relieve pain in myriad illnesses

and disorders. In addition, a CB1 antagonista compound

that blocks the receptor and renders it impotenthas worked

in some clinical trials to treat obesity. But though promising,

these drugs all have multiple effects because they are not spe-

cific to the region that needs to be targeted. Instead they go ev-

erywhere, causing such adverse reactions as dizziness, sleepi-

ness, problems of concentration and thinking abnormalities.

One way around these problems is to enhance the role of

the bodys own endocannabinoids. If this strategy is success-

ful, endocannabinoids could be called forth only under the

circumstances and in the locations in which they are needed,

thus avoiding the risks associated with widespread and in-

discriminant activation of cannabinoid receptors. To do this,

Piomelli and his colleagues are developing drugs that prevent

the endocannabinoid anandamide from being degraded after

it is released from cells. Because it is no longer broken down

quickly, its anxiety-relieving effects last longer.

Anandamide seems to be the most abundant endocannabi-

noid in some brain regions, whereas 2-AG dominates in others.

A better understanding of the chemical pathways that produce

each endocannabinoid could lead to drugs that would affect

only one or the other. In addition, we know that endocannabi-

noids are not produced when neurons fire just once but only

when they fire five or even 10 times in a row. Drugs could bedeveloped that would alter the firing rate and hence endocan-

nabinoid release. A precedent for this idea is the class of anti-

convulsant agents that suppress the neuronal hyperactivity un-

derlying epileptic seizures but do not affect normal activity.

Finally, indirect approaches could target processes that

themselves regulate endocannabinoids. Dopamine is well

known as the neurotransmitter lost in Parkinsons disease, but

it is also a key player in the brains reward systems. Many plea-

surable or addictive drugs, including nicotine and morphine,

produce their effects in part by causing dopamine to be released

in several brain centers. It turns out that dopamine can cause

the release of endocannabinoids, and various research teams

have found that two other neurotransmitters, glutamate and

acetylcholine, also initiate endocannabinoid synthesis and re-

lease. Indeed, endocannabinoids may be a source of effects

previously attributed solely to these neurotransmitters. Rather

than targeting the endocannabinoid system directly, drugs

could be designed to affect the conventional neurotransmit-

ters. Regional differences in neurotransmitter systems could be

exploited to ensure that endocannabinoids would be released

only where they were needed and in appropriate amounts.

In a remarkable way, the effects of marijuana have led to

the still unfolding story of the endocannabinoids. The receptor

CB1 seems to be present in all vertebrate species, suggesting

that systems employing the brains own marijuana have been

in existence for about 500 million years. During that time, en-

docannabinoids have been adapted to serve numerous, often

subtle, functions. We have learned that they do not affect the

development of fear, but the forgetting of fear; they do not alter

the ability to eat, but the desirability of the food, and so on.

Their presence in parts of the brain associated with complex

motor behavior, cognition, learning and memory implies thatmuch remains to be discovered about the uses to which evolu-

tion has put these interesting messengers.


Marijuana and Medicine. Edited by J. E. Joy, S. J. Watson, Jr., and J. A.Benson, Jr. Institute of Medicine, 1999.

Endocannabinoid Signaling in the Brain. R. I. Wilson and R. A. Nicoll inScience, Vol. 296, pages 678682; Apr il 26, 2002.

Retrograde Signaling in the Regulation of Synaptic Transmission:Focus on Endocannabinoids. B. E. Alger in Progress in Neurobiology,Vol. 68, No. 4, pages 247286; November 2002.

www.marijuana-info.org/

M O R E T O E X P L O R E

INDIAN FAKIRS prepare bha ng and ganja in this painting from the mid-1700s. The history of marijuana extends far back in history, with writtenrecords on its medical use appearing in ancient Chinese and Egyptiantexts. Discovery in the 1960s of its active component, THC, eventuallyled to identification of the brains own marijuana.


lecture 28 marijuana & nero transmitters

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